Immunobiology of human papillomavirus infection and vaccination - implications for second generation vaccines.

Prophylactic human papillomavirus (HPV) L1 virus like particle (VLP) vaccines have been shown, in large clinical trials, to be very immunogenic, well-tolerated and highly efficacious against genital disease caused by the vaccine HPV types. However these vaccines, at the present, protect against only two of the 15 oncogenic genital HPV types, they are expensive, delivered by intramuscular injection and require a cold chain. The challenges are to develop cheap, thermo-stable vaccines that can be delivered by non-injectable methods that provide long term (decades) protection at mucosal surfaces to most, if not all, oncogenic HPV types that is as good as the current VLP vaccines. Current approaches include L1 capsomers, L2 protein and peptides, delivery via recombinant L1 bacterial and viral vectors and large-scale VLP production in plants. Rational design and successful development of such vaccines will be based on an understanding of the immune response, and particularly the 'cross talk' between the innate and adaptive responses. This will be central in the development of adjuvants and vaccine formulations that induce the response to provide effective protection.

Trust in medical organizations predicts pandemic (H1N1) 2009 vaccination behavior and perceived efficacy of protection measures in the Swiss public

Following the recent avian influenza and pandemic (H1N1) 2009 outbreaks, public trust in medical and political authorities is emerging as a new predictor of compliance with officially recommended protection measures. In a two-wave longitudinal survey of adults in French-speaking Switzerland, trust in medical organizations longitudinally predicted actual vaccination status 6 months later, during the pandemic (H1N1) 2009 vaccination campaign. No other variables explained significant amounts of variance. Trust in medical organizations also predicted perceived efficacy of officially recommended protection measures (getting vaccinated, washing hands, wearing a mask, sneezing into the elbow), as did beliefs about health issues (perceived vulnerability to disease, threat perceptions). These findings show that in the case of emerging infectious diseases, actual behavior and perceived efficacy of protection measures may have different antecedents. Moreover, they suggest that public trust is a crucial determinant of vaccination behavior and underscore the practical importance of managing trust in disease prevention campaigns.

A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination.

Despite major progress in T lymphocyte analysis in melanoma patients, TCR repertoire selection and kinetics in response to tumor Ags remain largely unexplored. In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8(+) T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment. TCR sequencing also revealed that this particular clone arose at least 1 year before vaccination, displayed long-term persistence, and efficient homing to metastases. Remarkably, during concomitant vaccination over 3.5 years, the frequency of the pre-existing clone progressively increased, reaching up to 2.5% of the circulating CD8 pool while its effector functions were enhanced. In parallel, the disease stabilized, but subsequently progressed with loss of Melan-A expression by melanoma cells. Collectively, combined ex vivo analysis of T cell differentiation and clonality revealed for the first time a strong expansion of a tumor Ag-specific human T cell clone, comparable to protective virus-specific T cells. The observed successful boosting by peptide vaccination support further development of immunotherapy by including strategies to overcome immune escape.

Strategy selection: An introduction to the modeling challenge

Modeling the mechanisms that determine how humans and other agents choose among different behavioral and cognitive processes-be they strategies, routines, actions, or operators-represents a paramount theoretical stumbling block across disciplines, ranging from the cognitive and decision sciences to economics, biology, and machine learning. By using the cognitive and decision sciences as a case study, we provide an introduction to what is also known as the strategy selection problem. First, we explain why many researchers assume humans and other animals to come equipped with a repertoire of behavioral and cognitive processes. Second, we expose three descriptive, predictive, and prescriptive challenges that are common to all disciplines which aim to model the choice among these processes. Third, we give an overview of different approaches to strategy selection. These include cost‐benefit, ecological, learning, memory, unified, connectionist, sequential sampling, and maximization approaches. We conclude by pointing to opportunities for future research and by stressing that the selection problem is far from being resolved.

Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

Réduction de la consommation de sel: une mesure importante de santé publique en Suisse. [Reducing dietary salt intake: an important public health strategy in Switzerland]

La consommation actuelle de sel (chlorure de sodium) est très supérieure aux besoins physiologiques (1,5 g par jour, soit environ 550 mg par jour de sodium) dans la plupart des pays (> 8 g par jour). Les principales sources de sel sont les pains, les fromages, les produits dérivés de la viande et les plats précuisinés. En moyenne, une consommation élevée de sel est associée à une pression artérielle plus élevée. En Suisse, un adulte sur trois souffre d'hypertension artérielle. La moitié des accidents vasculaires cérébraux et des maladies cardiaques ischémiques sont attribuables à une pression artérielle trop élevée. L'Office fédéral de la santé publique conduit actuellement une stratégie visant à diminuer la consommation de sel dans la population suisse à moins de 5 g par jour sur le long terme (Salz Strategie 2008-2012). [Abstract] Current dietary salt (sodium chloride) intake largely exceeds physiological needs (about 1.5 g salt per day, or 550 mg sodium per day) in most countries (> 8 g salt per day). The main sources of dietar salt intake are breads, cheeses, products derived from meat and ready-to-eat meals. On average, a high-salt diet is associated with higher blood pressure levels. In Switzerland, one out of three adults suffers from arterial hypertension. Half of cerebrovascular events and ischaemic cardiac events are attributable to elevated blood pressure. The Swiss Federal Office of Public Health is currently running a strategy aiming at reducing dietary salt intake in the Swiss population to less than 5 g per day on the long run (Salz Strategie 2008-2012).

Iowa Strategy for Homeland Security and Emergency Management 2015-2017, October 1, 2014

Address sustainability in all efforts. Sustainability should be at the core of all levels of homeland security and emergency management effort in Iowa. Capabilities need to be built for the long term, and without a sustainability plan in place, projects can quickly deplete uncertain levels of funding. Utilize an all-hazards methodology. Developing capabilities that are effective during a variety of disaster and emergency scenarios represents sound planning and resource management. Enhance capabilities through joint planning, training and exercise. Effective capabilities developed through coordinated planning efforts and an ongoing joint training and exercising program to ensure substantiate of prepared response. Utilize a collaborative approach to build capability. We will utilize whatever partnerships are necessary to build capability in the most effective manner possible. Regional partnerships have been, and will continue to be, in the forefront of the State of Iowa’s efforts to build and enhance capability. Enhance statewide capabilities. Whenever possible, we will identify and augment existing resources to provide statewide capability during a disaster or terrorist attack. Awareness, outreach and education. Open communication is critical to the success of any initiative. All projects implemented will have awareness, education and outreach components to ensure that all stakeholders are informed as to their responsibilities, capabilities and access. Information sharing and a common operating picture. The timely exchange of critical/actionable information is imperative to the success of every operation. The identification of a common operating picture allows decision makers to make informed decisions based on a unified understanding of the events around them.

Management Strategy for Iowa’s Water Resources, December 2007

In Iowa, the Department of Natural Resources (DNR)is responsible for regulating water allocation and use through the issuance of water use permits, but improvements are necessary in this process to assure sustainable supplies into the future. In recent years, there have not been resources dedicated at the state level to properly track and assess water quantity issues. Resources for water use and water quantity monitoring (groundwater level and surface gauges) have continued to decline and have resulted in data becoming outdated and in a format that is difficult to analyze in order to make good decisions.

Immunogenicity and safety of yellow fever vaccination for 102 HIV-infected patients.

BACKGROUND: Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. METHODS: In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1:<10 were defined as nonreactive, which was considered to be nonprotective. The results were compared with data for HIV-uninfected individuals. Serious adverse events were defined as hospitalization or death within 6 weeks after receipt of 17DV. RESULTS: At the time of 17DV administration, the median CD4 cell count was 537 cells/mm(3) (range, 11-1730 cells/mm(3)), and the HIV RNA level was undetectable in 41 of 102 HIV-infected patients. During the first year after vaccination, fewer HIV-infected patients (65 [83%] of 78; P = .01) than HIV-uninfected patients revealed reactive NTs, and their NTs were significantly lower (P < .001) than in HIV-uninfected individuals. Eleven patients with initially reactive NTs lost these reactive NTs <or= 5 years after vaccination. Higher NTs during the first year after vaccination were associated with undetectable HIV RNA levels, increasing CD4 cell count, and female sex. We found no serious adverse events after 17DV administration among HIV-infected patients. CONCLUSION: Compared with HIV-uninfected individuals, HIV-infected patients respond to 17DV with lower reactive NTs, more often demonstrate nonprotective NTs, and may experience a more rapid decline in NTs during follow-up. Vaccination with 17DV appears to be safe in HIV-infected individuals who have high CD4 cell counts, although rate of serious adverse events of up to 3% cannot be excluded.

Endosperm genotyping as a strategy to differentiate the allele source in maize heterozygous progeny

The objective of this work was to distinguish the parental source of alleles in heterozygous progeny using semiquantitative polymerase chain reaction (PCR) in maize endosperm. Endosperms derived from direct and reciprocal single-cross hybrids between maize inbred lines L3 and L1113-01 were genotyped by semiquantitative PCR methodology (SQ-PCR) using fluorescent microsatellite primers. The amplification products were evaluated by the ratios of fluorescence intensity (RFI), calculated between the peaks corresponding to the alleles derived from each parental line. Based on the statistically significant contrast between RFI mean values of direct and reciprocal single-cross hybrids, it was possible to distinguish the number of alleles received from each parental line and, ultimately, to determine the origin of the alleles of each cross. Thus, endosperm genotyping using SQ-PCR is a promising strategy to map QTL in maize outbred populations.

Quantification of the diversity among common bean accessions using Ward-MLM strategy

The present work aimed at evaluating the divergence among common bean accessions by their agronomic, morphological and molecular traits, based on the Ward-MLM procedure. A collection of 57 accessions from the gene bank of Universidade Federal do Espírito Santo was used in this study, from which: 31 were landraces belonging to the community Fortaleza, in the municipality of Muqui, ES, Brazil; 20 accessions were provided by Embrapa Trigo; and 6 were commercial cultivars. Five agronomic traits (plant cycle, number of seeds per pod, number of pods per plant, weight of 100 seeds, and grain yield), five morphological traits (growth habit, plant size, seed shape, seed color, and commercial group) and 16 microsatellite primers were evaluated. High genetic variability was detected considering morphological, agronomic and molecular traits in the 57 common bean accessions studied. The Ward-MLM procedure showed that the ideal number of groups was five, according to the pseudo F and pseudo t² criteria. The accessions from Andean origin had heavier seeds than others and formed a cluster. The Ward-MLM statistical procedure is a useful technique to detect genetic divergence and to cluster genotypes by simultaneously using morphological, agronomic and molecular data.

Minimization of Nyquist ghosting for echo-planar imaging at ultra-high fields based on a "negative readout gradient" strategy.

PURPOSE: To improve the traditional Nyquist ghost correction approach in echo planar imaging (EPI) at high fields, via schemes based on the reversal of the EPI readout gradient polarity for every other volume throughout a functional magnetic resonance imaging (fMRI) acquisition train. MATERIALS AND METHODS: An EPI sequence in which the readout gradient was inverted every other volume was implemented on two ultrahigh-field systems. Phantom images and fMRI data were acquired to evaluate ghost intensities and the presence of false-positive blood oxygenation level-dependent (BOLD) signal with and without ghost correction. Three different algorithms for ghost correction of alternating readout EPI were compared. RESULTS: Irrespective of the chosen processing approach, ghosting was significantly reduced (up to 70% lower intensity) in both rat brain images acquired on a 9.4T animal scanner and human brain images acquired at 7T, resulting in a reduction of sources of false-positive activation in fMRI data. CONCLUSION: It is concluded that at high B(0) fields, substantial gains in Nyquist ghost correction of echo planar time series are possible by alternating the readout gradient every other volume.